The Role of Obesity in Cancer

Inhaltsverzeichnis

1. Introduction

2. Background
2.1 Obesity
2.1.1 Factors contributing to obesity
2.1.2 Genetics, Obesity and the Environment
2.1.3 Role of Hormones in Obesity
2.1.4 Human Microbiome and Obesity
2.1.5 Metabolism and Obesity
2.2 Epidemiology of Obesity

3. Discussion
3.1 The correlation of obesity and cancer: a metabolic study
3.2 Analytical Epidemiological Studies on Obesity and Cancer
3.3 Intervention Trials on Obesity and Cancer
3.4 Experimental studies on Obesity and Cancer
3.5 Cancer and Obesity in perspective of Epidemiology

4. Conclusion

References

Abstract

Obesity is a known cause of cancer, with worldwide research and epidemiological studies supporting the relationship between obesity and cancer. Obesity can lead to a number of cancers, through cellular and metabolic changes in the body. Hyperinsulenimia, low levels of estrogens and Insulin like growth factor binding protein-3 (IGF-BP3) are among the major causes of cancers that result from obesity. In this study we aim at reviewing the metabolic changes that accompany obesity and cancer, the molecular mechanisms associated with obesity and cancer and finally the epidemiological significance of this relationship.

1. Introduction

Obesity is a well established cause of cancer, with worldwide research and epidemiological studies being carried out in order to further appropriate the relationship between obesity and cancer. In order to better understand the role of obesity in cancer we must first fully understand the underlying causes of obesity that lead to changes in biochemistry, physiology and cellular functioning of an individual that aggregate to cancer. There is a need to fully understand the implications of obesity in causing cancer, especially breast cancer in post menopausal women. In this study we aim at reviewing the main causatives of cancer and obesity, the molecular mechanisms that turn obesity into cancer and the epidemiological significance of this relationship.

2. Background

2.1 Obesity

Obesity is defined as an excessive or abnormal accumalation of body fat in dangerous levels that pose a threat to health and quality of life. Being overweight is different from obesity, overweight means that the body weighs more than the normal range which can be in the form of bone, muscle mass or fat. However obesity directly relates to the abonormal body fat accumalation. A rough scale that can give an estimate of obesity can be calculated by Body Mass Index (BMI), which is obtained when a person’s weight (in kg) is divided by height (meters). A BMI of 30 or more is genreally considered to be in the obese range, while the BMI of an overweight person is usually more than 25 (K. M. Flegal 2013). Obesity is a medical condition which leads to several other chronic disorders such as coronary heart disease, musculoskeletal diseases, diabetes and cancer.

2.1.1 Factors contributing to obesity

The most obvious and main cause of obesity is metabolic imbalance between calories consumed and calories burnt. A calorie is defined as the amount of energy needed to raise the temperature of water by one degree celcius. This, in turn, results in an excessive accumalation of body fat and with the course of time pounds of fat build up in the body. Global trends in food consumption indicate foods that have higer fat content (such as fast foods), an overall decrease in physical activity due to change in working trends and technological development, the evolution of modes of transportation and finally the increasing rate of urbanization contribute to obesity (K. M. Flegal 2013). Although genes are responsible for obesity they play a much smaller role than previously thought. Obesity related genes aggravate obesity be interacting with other environmental factors such as physical activity and diet (K. M. Flegal 2013).

2.1.2 Genetics, Obesity and the Environment

A gene-enviornment interaction is a phenomenon where the genotyoe of an individual defines the relative response or behaviour to any external environmental factor. When it comes to studying the effects of obesity there are two main categories of gene-environment interaction, namely geneotype-nutrition and genotype-physical activity interaction. In order to observe the effects of obesity on the types of interactions pair of –mono and dizygotic twins are studied for the influence of external environmental factors on obesity, besides the obvious genetic code. Through polymorphism and genetic studies on mono and dizygotic twins it has been possible to identify point mutations and genes responsible for the pathophysiology of obesity. Single genes that have been identified as regualtors of obsesity are: LEP, LEPR, POMC, PSCK1, SIM1, MC3R, MC4R, CRHR1, CRHR2, SIM1 and GRP24 (C. Bouchard 2008). These genes were identified through genetic screening in individuals that were heavily obese with an early onset of obesity. Furthermore loci for obsity related genes that have a Mendelian pattern of heredity have also been identified (C. Bouchard 2008). Interaction of environment with obesity related genes was identified in a study by Bouchard, et al, 1990 where 12 pairs of twins (male) had an intake of 1000 calories surplus in their diet for a period of 6 days per week for a period of hundred days. The results of the study indicated a significant relationship between excess calories and individual responses. Furthermore the genetic variation was not random but it was observed as a significant within-pair resenblance in response. The study indicated that if other variables such as geneteic makeup and life style remain constant; even then certain individuals have a greater tandency to accumalate fat as compared to others. Also there is a likely genetic basis for the body fat storage tandency (C. e. Bouchard 1990).

2.1.3 Role of Hormones in Obesity

There has been extensive research in the role of hormones as causative of obesity. Changing levels of estrogen have been implicated in regulation of overall body weight (Blüher 2013). Two types of estrogen receptors ERα and ERβ are expressed in periperal tissues including adipose cells, where these receptors may play a role in adipose accumalation and inflammation (Blüher 2013). A human polymorphism (Xbal) has been identified in the ERα gene which has a substitution of guanidine with adenine in exon-1 (Okura T 2003). A comparative study was conducted on two thousand pre-menopausal Japanese women that had an increased adipic mass and fat around the waist line and that had the polymorphism, in conrast to the women with the normal polymorphism. The results of the study indicate a relation of the polymorphism in the ERα gene with increased fat deposition in periperal adipose tissues (Okura T 2003). Another key metabolism regulating enzyme is leptin, which gives a powerful signal to the central nervous syetem. This results in a catabolic burst, involves limiting food intake and maximizing energy expenditure. Leptin is secreted by by adipose cells and its amount is directly linked to the amount of adipose tissue present in the body. The main modulator of leptin is estrogen; higher levels of estrogen during estrous and metestrous stages leads to higher catabolic sensitivity of leptin. Exogenous administration od estradiol-17β, in mice leads to in increased sensitivity to leptin as compared to controls (E. E. Calle 2004).

2.1.4 Human Microbiome and Obesity

The lower gastro-intestinal tract hosts a wide array of micro-organisms that help in the breakdown of several important nutritional components in the diet that would otherwise be indigestible. Several studies indicate slight differences in the gut microbiota of healthy adults through the sequencing and measurement of the 16S RNA expression of the bacterial population of the gut. There have been studies that indicate that miniscule variations in the gut flora are indicative of obesity and a normal body weight. In order to judge the role of microbiota in obesity, Turnbaugh, et al, (2009) characterized microbial communities housed by monozygotic and dizygotic twins by sequencing the 16S RNA gene. Although the micro-organisms of family members had almost the same core-microbiome, obesity was caused by phylum-level changes in the gut micro-organisms. Since the cause of obesity was a phylum level change in bacteria this means that bacteria from different phyla have very different metabolic pathways for degradation. The altered degradation pathways meant that different individuals will be able to degrade a single nutrient through different pathways. In conclusion deviations from the core-microbiome at the phylum level can predispose an individual towards obesity (Turnbaugh 2009).

2.1.5 Metabolism and Obesity

Circulating hormones such as insulin and steroid hormones have a profound effect on body metabolism and ultimately body weight. An increased BMI is indicative of a high level of circulating insulin and the amount of insulin increases with the increase in BMI. The main role of insulin is to balance the amount of excessive carbohydrates at the cellular level. Consumption of sugary foods lead to production of high levels of insulin a condition called hyper-insulinemia that ultimately leads to a state of insulin resistance. Obesity is attributed to hyperinsulinemia and insulin resistance (E. M. Calle 2004).

Obesity and insulin resistance as key players in weight gain have been studied across all ethnic groups and sufficient data has been collected for almost all body weights. As the BMI (fat deposition in the body) rises, so does the risk for insulin resistance and consequently of obesity. This implies that the amount of body fat present within the body has an important effect on insulin sensitivity (Kahn 2000).

2.2 Epidemiology of Obesity

A recent survey (2007-2008) by the National Health and Nutrition Examination Survey (NHANES) places the number of obese individuals at 68% who are 20 years or older (Ogden 2010). This is in contrast much higher than the survey carried out from 1988-1994 which reported 56% of adults above 20 as obese in the U.S (Crespo 2001). But this is not even half of the story since high percentages of obesity have been reported in young children (ages 2-19). The survey data on children puts the level of obese children at 17% based on a recent survey from 2007-2008 (Ogden 2010); which is much higher than the survey conducted from 1988-1994 that indicated obesity levels at 10% (Crespo 2001). Correlation studies between obesity and cancer have also seen a gradual increase in occurrences of obesity related cancers. An analytical study by Hock, et al., (2002) data from NCI Surveillance, Epidemiology, and End Results (SEER) gave an estimate that in 2007, in the U.S, 34,000 new cancer cases in men and 50,500 in women were reported that were obesity related. Recent broad survey data suggests that obesity is a leading cause of a wide range of cancers including esophagus, colon, breast, kidney and thyroid (Gilbert 2013).

3. Discussion

Obesity and eating habits account for almost 30% of the cancers in developed western countries, thus making obesity the second largest cause of cancer, after tobacco (E. E. Calle 2004). However, in developing countries the rate of cancer related to obesity is much lower and accounts for 20% of cancers (E. E. Calle 2004). Research into obesity that leads to cancer has lead to some certain facts and also some unanswered questions. In this discussion, the metabolic imbalance that lead to cancer, epidemiological studies, intervention trials, experimental studies, epidemiology and gender distribution of cancer. Furthermore, different types of cancers, which are caused by obesity, are also discussed.

3.1 The correlation of obesity and cancer: a metabolic study

There has been incresing evidence that the body weight has serious effects on the levels of circulating steroid and peptide hormones. These hormones have the capability to play a major role in cancer. A cross sectional study on obesity shows that there is an increase of insulin and Insulin like growth factor-binding protein 3 (IFGBP-3) in both males and females. Furthermore there is a decrease in IGF-1, human growth hormone and sex hormone binding protein. Also there is an increase of circulating estradiol in males and post-menopausal women under obese conditions (IARC 2011).

Perhaps one of the most noticeable increase is of insulin, in obesity. A linear increase has been observed in circulating levels of insulin which directly correlates with the BMI of the individual. Insulin is a peptide based hormone, which is secreted when blood sugar levels increase and acts to limit and control the uptake of glucose by peripheral tissues. When the body is continually subjected to large meals, over-eating and excessive consumption, the body assumes a state of chronic hyperinsulinemia. Abdominal obesity, in particular arises from hyperinsulinemia and subsequent insulin resistance (Braun 2011).

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